We have developed genetically engineered herpes simplex virus-1 (HSV-1) vectors that can selectively and efficiently infect and kill brain tumor cells in situ without harming surrounding brain cells and without causing systemic disease. Having taken one such vector into human clinical trial, we are currently planning a second trial based on our recently published data demonstrating that cancer cell DNA repair pathways can be used in conjunction with specific HSV gene mutations and chemotherapeutics to increase the efficacy of herpes oncolytic viral therapy for brain tumor therapy. The current grant proposal both builds upon the findings of the past grant period as well as explores other cancer cell mechanisms that also may be utilized in conjunction with appropriate Pharmaceuticals to improve oncolytic viral efficacy. In order to increase the efficacy of HSV oncolysis in brain tumor therapy, we hypothesize that: 1: HSV vectors directly expressing GADD34 or indirectly inducing GADD34 expression will have increased efficacy in tumor cells. We will create vectors expressing GADD34 as well as vectors containing transgenes that may act as regulators of GADD34. 2: The efficacy of oncolytic HSV therapy can be increased by combination with chemotherapeutic drugs inhibiting topoisomerases or microtubules. Both of these classes of drugs interact with the virus and the tumor cells and may be avenues for novel therapeutic synergy. 3. Targeting the tumor vasculature using "armed" anti-angiogenic oncolytic HSV vectors in conjunction with appropriate Pharmaceuticals will further improve therapeutic efficacy. We have demonstrated that a combined attack on both the tumor cells and the tumor vasculature can increase anti-tumor efficacy. We have already created several HSV vectors expressing anti-angiogenic genes. We have also developed a rapid method for vector creation to allow for the testing of additional anti-angiogenic genes. Additional "armed" vectors will be created and we will test their efficacy in vitro and animal brain tumor models. Additionally, we will investigate the interactions of HSV with anti-angiogenic Pharmaceuticals with our vectors. Upon completion of this proposal, we anticipate that one or more of these strategies will be in a position to be translated into a clinical trial for the therapy of malignant glioma.